Estaras Matias, Gonzalez-Portillo Manuel R, Martinez Remigio, Garcia Alfredo, Estevez Mario, Fernandez-Bermejo Miguel, Mateos Jose M, Vara Daniel, Blanco-Fernández Gerardo, Lopez-Guerra Diego, Roncero Vicente, Salido Gines M, Gonzalez Antonio
Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain.
Department of Animal Health, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain.
Antioxidants (Basel). 2021 Apr 8;10(4):577. doi: 10.3390/antiox10040577.
Pancreatic stellate cells (PSC) play a major role in the formation of fibrotic tissue in pancreatic tumors. On its side, melatonin is a putative therapeutic agent for pancreatic cancer and inflammation. In this work, the actions of melatonin on PSC subjected to hypoxia were evaluated. Reactive oxygen species (ROS) generation reduced (GSH) and oxidized (GSSG) levels of glutathione, and protein and lipid oxidation were analyzed. The phosphorylation of nuclear factor erythroid 2-related factor (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and the regulatory protein nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα) was studied. The expression of Nrf2-regulated antioxidant enzymes, superoxide dismutase (SOD) enzymes, cyclooxygenase 2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also studied. Total antioxidant capacity (TAC) was assayed. Finally, cell viability was studied. Under hypoxia and in the presence of melatonin generation of ROS was observed. No increases in the oxidation of proteins or lipids were detected. The phosphorylation of Nrf2 and the expression of the antioxidant enzymes catalytic subunit of glutamate-cysteine ligase, catalase, NAD(P)H-quinone oxidoreductase 1, heme oxygenase-1, SOD1, and of SOD2 were augmented. The TAC was increased. Protein kinase C was involved in the effects of melatonin. Melatonin decreased the GSH/GSSG ratio at the highest concentration tested. Cell viability dropped in the presence of melatonin. Finally, melatonin diminished the phosphorylation of NF-kB and the expression of COX-2, IL-6, and TNF-α. Our results indicate that melatonin, at pharmacological concentrations, modulates the red-ox state, viability, and the expression of proinflammatory mediators in PSC subjected to hypoxia.
胰腺星状细胞（PSC）在胰腺肿瘤纤维化组织的形成中起主要作用。另一方面，褪黑素是一种用于胰腺癌和炎症的潜在治疗剂。在这项研究中，评估了褪黑素对处于缺氧状态的PSC的作用。分析了活性氧（ROS）的产生、谷胱甘肽的还原型（GSH）和氧化型（GSSG）水平以及蛋白质和脂质氧化情况。研究了核因子红细胞2相关因子（Nrf2）、活化B细胞的核因子κ轻链增强子（NF-κB）以及B细胞中κ轻多肽基因增强子的调节蛋白核因子抑制剂α（IκBα）的磷酸化情况。还研究了Nrf2调节的抗氧化酶、超氧化物歧化酶（SOD）、环氧合酶2（COX-2）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达。测定了总抗氧化能力（TAC）。最后，研究了细胞活力。在缺氧条件下且存在褪黑素时观察到了ROS的产生。未检测到蛋白质或脂质氧化增加。Nrf2的磷酸化以及谷氨酸-半胱氨酸连接酶催化亚基、过氧化氢酶、NAD（P）H-醌氧化还原酶1、血红素加氧酶-1、SOD1和SOD2等抗氧化酶的表达增加。TAC升高。蛋白激酶C参与了褪黑素的作用。在测试的最高浓度下，褪黑素降低了GSH/GSSG比值。在存在褪黑素的情况下细胞活力下降。最后，褪黑素减少了NF-κB的磷酸化以及COX-2、IL-6和TNF-α的表达。我们的结果表明，在药理浓度下，褪黑素可调节处于缺氧状态的PSC的氧化还原状态、活力和促炎介质的表达。
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